Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice

Aging clocks, based on age-dependent DNA methylation changes, allow age determination and assess intervention efficacy in aging processes. Despite debates on programmed aging, this study supports an evolutionary aging theory where stochastic variation accumulates post-reproduction, predicting age accurately. It suggests any data with a ground state at age zero can build accurate aging clocks.

Lifespan of aged mice was extended through systemic delivery of AAVs encoding an OSK system. The mice, at 124 weeks old, experienced a remarkable 109% increase in median remaining lifespan compared to wild-type controls. This intervention also improved various health parameters and frailty scores, suggesting the potential to enhance both lifespan and healthspan in aging individuals. Furthermore, significant epigenetic markers of age-reversal were observed in human keratinocytes expressing exogenous OSK, indicating the possibility of reversing age-related changes. These findings have significant implications for developing interventions to combat age-associated diseases in the elderly.

A mathematical model proposes that mortality results from two opposing processes: physiological decline with age and survival benefits from growth and learning. Simulations show learning accelerates slower aging but limits negligible senescence. These findings shed light on the complex relationship between learning, mortality, and aging evolution.

BIOIO-1001, identified in a CRISPRa screen, impacts lipid metabolism via SIRT3 which intersects two key aging pathways, the mTOR/insulin and NAD+ pathways. In vivo testing reduced metabolic issues, inflammation, and fibrosis in NASH and ALS models, making it a versatile therapy fitting the geroscience hypothesis.